疾患詳細

疾患詳細





#274150
Thrombotic thrombocytopenic purpura, hereditary (TTP)
(Thrombotic thrombocytopenic purpura, hereditary, infantile- or adult onset)
(Thrombotic thrombocytopenic purpura, congenital)
(Microangiopathic hemolytic anemia)
(Thrombotic microangiopathy, familial)
(Upshaw-Schulman syndrome; USS)
(Schulman-Upshaw syndrome)
(Upshaw factor, deficiency of)
(Microangiopathic hemolytic anemia, congenital)
(Thrombotic thrombocytopenic purpura, familial)

血栓性血小板減少性紫斑病, 遺伝性
(血栓性血小板減少性紫斑病, 遺伝性, 乳児または成人発症)
(血栓性血小板減少性紫斑病, 先天性)
(微小血管症性溶血性貧血)
(血栓性微小血管症, 家族性)
(Upshaw-Schulman 症候群)
(Schulman-Upshaw 症候群)
(Upshaw 因子欠乏症)
(微小血管症性溶血性貧血, 先天性)
(血栓性血小板減少性紫斑病, 家族性)
指定難病64 血栓性血小板減少性紫斑病

責任遺伝子:604134 A disintegrin-like and metalloprotease with thrombospondin type 1 (ADAMTS13) <9q34.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
<5%-29%>
 Respiratory distress (呼吸窮迫) [HP:0002098] [01606]

 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Confusion (昏迷) [HP:0001289] [0151]
 Elevated serum creatinine (血清クレアチニン上昇) [HP:0003259] [2092]
 Fever (発熱) [HP:0001945] [01413]
 Hemolytic-uremic syndrome (溶血性尿毒症候群) [HP:0005575]
 Increased blood urea nitrogen (BUN増加) [HP:0003138] [0196]
 Increased serum lactate (乳酸増加) [HP:0002151] [2044]
 Jaundice (黄疸) [HP:0000952] [01810]
 Microangiopathic hemolytic anemia (微小血管障害性溶血性貧血) [HP:0001937] [2202]
 Microscopic hematuria (顕微血尿) [HP:0002907 ] [0193]
 Prolonged neonatal jaundice (遷延性新生児黄疸) [HP:0006579] [01810]
 Proteinuria (蛋白尿) [HP:0000093] [0197]
 Reticulocytosis (網状赤血球症) [HP:0001923] [2215]
 Schistocytosis (分裂赤血球増加) [HP:0001981] [2202]
 Thrombocytopenia (血小板減少) [HP:0001873] [2218]
 Tremor (振戦) [HP:0001337] [02604]

(UR-DBMS)
【一般】急性呼吸窮迫症候群 (まれ)
 腎機能障害
 発熱
 黄疸, 新生児
【神経】変動する神経症状
 巣状の神経症状
 意識障害
 混乱
 振戦
【検査】ヘモグロビン低値
 血清 lactate dehydrogenase (LDH) 増加
 血清 haptoglobin 減少
 蛋白尿
 顕微血尿
 BUN 高値
 クレアチニン増加
血漿の非常に大きな von Willebrand 因子 (UL-vWF)
【血液】出血傾向
 血栓症
 血小板減少 (10万/µL未満),
 紫斑
 微小血管症性溶血性貧血 (Hb <12g/dL), 直接クームス試験陰性
 網状赤血球症
 Schistocytes

<指定難病 血栓性血小板減少性紫斑病>
1.概要
 血栓性血小板減少性紫斑病(thrombotic thrombocytopenic purpura:TTP)は, 1924年米国のEli Moschcowitzによって初めて報告された疾患で, 歴史的には1)消耗性血小板減少, 2)微小血管症性溶血性貧血, 3)腎機能障害, 4)発熱, 5)動揺性精神神経障害の古典的5徴候で診断されていた。
 その後, 1)2)のみの症例でも同様の病態であることが報告されてきたが, より最近ではADAMTS13活性著減(10%未満)のみがTTPと診断されるようになった。TTPの罹患年令は新生児から老人までと幅広く, 日本国内では30~50歳と60歳前後に発症ピークが認められる。罹患率は女性にやや多いが, 30~50歳では女性が明らかに多く, 高齢になれば男性の比率が高まる。
 
2.原因
 ADAMTS13の基質であるフォンウィルブランド因子(von Willebrand factor:VWF)は, 血管内皮細胞で超高分子量VWF多重体(UL-VWFM)として産生され, 内皮細胞内に蓄積される。この後, 一部は血管内皮下組織に分泌されマトリックスの構成成分となるが, 残りの大部分は, 様々な刺激によって内皮細胞から血中に放出される。この時, UL-VWFMはその特異的切断酵素ADAMTS13によって切断され小分子化し, 止血に適した分子型となる。したがって, ADAMTS13活性が著減するとUL-VWFMが切断されず, 血中に蓄積し, 末梢細動脈等で生じる高ずり応力下に過剰な血小板凝集が引き起こされ, 血栓を生じる。
 
3.症状
 先天性TTPであるアップショー・シュールマン症候群(Upshaw-Schulman症候群:USS)は, 生後間もなく新生児重症黄疸で発症する典型的な症例があるが, 学童期に繰り返す血小板減少で診断される症例や, 成人期以降に習慣性流産などの妊娠時に発症するタイプもある。この発症年齢の差が何故なのかはいまだ不明である。しかし, 最近になって小児期に特発性血小板減少性紫斑病(ITP)と誤って診断されている症例で, 妊娠を契機にTTPを発症し, USSであると診断された例が多く報告されている。後天性TTPでは, 体のだるさ, 吐き気, 筋肉痛などが先行し, 発熱, 貧血, 出血(手足に紫斑), 精神神経症状, 腎障害が起こる。発熱は38℃前後で, ときに40℃を超えることもあり, 中等度ないし高度の貧血を認め, 軽度の黄疸(皮膚等が黄色くなる。)を伴うこともある。精神神経症状として, 頭痛, 意識障害, 錯乱, 麻痺, 失語, 知覚障害, 視力障害, 痙攣などが認められる。血尿, 蛋白尿を認め, まれに腎不全になる場合もある。
 
4.治療法
 先天性TTP(USS):新鮮凍結血漿(FFP)を定期的に輸注してADAMTS13酵素補充を行い, 血小板数を維持する治療が行われる。将来は, 現在臨床治験が行なわれている遺伝子組換え蛋白(rADAMTS13)による酵素補充療法が可能となると思われる。
 後天性TTP: ADAMTS13インヒビター(自己抗体)によってADAMTS13活性が著減しているので, FFPのみの投与では不十分で, 治療は血漿交換(PE)療法が第一選択となる。この際, ステロイド又はステロイドパルス療法の併用が一般的である。
 TTPの血小板減少に対して, 血小板輸血を積極的に行うことは「火に油をそそぐ(fuel on the fire)」に例えられ, 基本的には予防的血小板輸血は禁忌となる。また, 難治・反復例に対してはビンクリスチン, エンドキサンなどの免疫抑制剤の使用や脾摘なども考慮される。最近では, 抗CD20キメラ抗体であるリツキサンがPEに治療抵抗性を示し, かつ高力価ADAMTS13インヒビターを認める症例に極めて有用との報告が数多くなされている。

5.予後
無治療では2週間以内に約9割が血栓症のため死亡する。血漿交換療法を速やかに開始すれば, 約8割は生存可能である。再発・難治例は血漿交換療法が無効なことも多い。

<指定難病診断基準>
他に原因を認めない血小板減少を認めた場合, ADAMTS13活性を測定し10%未満に著減している症例をTTPと診断する。
抗ADAMTS13自己抗体が陽性であれば後天性TTPと診断する。陰性であればUSSと診断する。

(補足)
TTPを疑う5徴候を認めるがADAMTS13活性が著減していない症例は現在の診断基準ではTTPではないが, 直ちに血漿交換などの治療が必要な症例が存在する。

TTPを疑う徴候の目安
① 血小板減少
 血小板数が10万/µL未満。1~3万/µLの症例が多い。
② 微小血管症性溶血性貧血
 微小血管症性溶血性貧血は, 赤血球の機械的破壊による貧血で, ヘモグロビンが12g/dL未満(8~10g/dLの症例が多い)で溶血所見が明らかなこと, かつ直接クームス試験陰性で判断する。
 溶血所見とは, 破砕赤血球の出現, 間接ビリルビン, LDH, 網状赤血球の上昇, ハプトグロビンの著減などを伴う。
③ 腎機能障害
 尿潜血や尿蛋白陽性のみの軽度のものから血清クレアチニンが上昇する症例もあり。ただし, 血液透析を必要とする程度の急性腎不全の場合は溶血性尿毒症症候群(HUS)が疑われる。
④ 発熱
 37℃以上の微熱から39℃台の高熱まで認める。
⑤ 動揺性精神神経症状
 頭痛など軽度のものから, せん妄, 錯乱などの精神障害, 人格の変化, 意識レベルの低下, 四肢麻痺や痙攣などの神経障害などを認める。

除外すべき疾患
① 播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)
 TTP症例では, PT, APTTは正常で, フィブリノゲン, アンチトロンビンは低下しないことが多く, FDP, D-dimerは軽度の上昇にとどまることが多い。DICの血栓は, フィブリン/フィブリノゲン主体の凝固血栓であり, APTTとPTが延長し, フィブリノゲンが減少する。
② 溶血性尿毒症症候群(hemolytic uremic syndrome:HUS)
 腸管出血性大腸菌(O157など)感染症による典型HUSは, 便培養検査・志賀毒素直接検出法(EIA)などの大腸菌の関与を確認する方法や抗LPS(エンドトキシン)IgM抗体などで診断する。
③ HELLP症候群
 HELLP症候群とは, 妊娠高血圧腎症や子癇で, 溶血(hemolysis), 肝酵素の上昇(elevated liver-enzymes), 血小板減少(low platelets)を認める多臓器障害である。
 診断は, Sibaiらの診断基準(Sibai BM,et al.Am J Obstet Gynrcol 1993;169:1000)によって行われるが, この基準ではTTPとの鑑別が困難である。ADAMTS13活性が著減していればTTPと診断する。
①    エヴァンズ(Evans)症候群
 Evans症候群では直接クームス陽性である。ただし, クームス陰性エヴァンズ症候群と診断されることがあるが, このような症例の中からADAMTS13活性著減TTPが発見されている。

補足
 抗ADAMTS13インヒビターをベセスダ法で測定し, 1単位/mL以上は明らかな陽性と判断できる。しかし, 陰性の判断は必ずしも容易ではなく, USSの診断は両親のADAMTS13活性測定などを参考に行うが, 確定診断にはADAMTS13遺伝子解析が必要である。
 USS患者の両親は, ヘテロ接合体異常であることからADAMTS13活性は30から50%を示す場合が多い。
 なお, ADAMTS13自己抗体は, 中和抗体(インヒビター)を測定することが一般的であり, 研究室レベルでのみ非中和抗体の検査が可能である。

(Responsible gene) *604134 A disintegrin-like and metalloprotease with thrombospondin type 1 (ADAMTS13) <9q34.2>
.0001 Thrombotic thrombocytopenic purpura, hereditary (274150) [ADAMTS13, HIS96ASP] (rs121908467) (RCV000006154) (Levy et al. 2001)
.0002 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, CYS951GLY] (rs121908468) (RCV000006155) (Levy et al. 2001)
.0003 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ARG102CYS] (rs121908469) (gnomAD:rs121908469) (RCV000006156) (Levy et al. 2001)
.0004 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, THR196ILE] (rs121908470) (gnomAD:rs121908470) (RCV000006157) (Levy et al. 2001)
.0005 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ARG398HIS] (rs121908471) (gnomAD:rs121908471) (RCV000006158) (Levy et al. 2001)
.0006 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, CYS1024GLY] (rs121908472) (gnomAD:rs121908472) (RCV000006159) (Levy et al. 2001)
.0007 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ARG528GLY] (rs121908473) (gnomAD:rs121908473) (RCV000006160) (Levy et al. 2001)
.0008 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 1-BP INS, 3769T] (rs387906341) (RCV000006161) (Levy et al. 2001)
.0009 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 25-BP DEL, NT2376] (rs387906342) (RCV000006162) (Levy et al. 2001)
.0010 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, CYS1213TYR] (rs121908474) (gnomAD:rs121908474) (RCV000006164) (Levy et al. 2001)
.0011 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ARG692CYS] (rs121908475) (gnomAD:rs121908475) (RCV000006165) (Levy et al. 2001)
.0012 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, IVS13DS, G-A, +5] (RCV000006166) (Levy et al. 2001)
.0013 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, GLN449TER] (rs121908476) (gnomAD:rs121908476) (RCV000006167) (Kokame et al. 2002)
.0014 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ARG268PRO] (rs121908477) (RCV000006168) (Kokame et al. 2002)
.0015 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, GLN448GLU AND CYS508TYR] (rs281875305) (rs2301612) (gnomAD:rs281875305) (gnomAD:rs2301612) (RCV000006169...) (Kokame et al. 2002)
.0016 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, PRO475SER] (rs11575933) (gnomAD:rs11575933) (RCV000006170...) (Kokame et al. 2002)
.0017 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 2-BP DEL, 1783TT] (rs387906344) (RCV000006171) (Savasan et al. 2003)
.0018 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 1-BP INS, 4143A] (rs387906343) (RCV000006163) (Pimanda et al. 2004)
.0019 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, IVS4DS, G-A, +1 ] (rs786205077) (RCV000006173) (Matsumoto et al. 2004)
.0020 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, ALA250VAL] (rs121908478) (RCV000006174) (Uchida et al. 2004)
.0021 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, IVS3DS, G-A] (rs786205078) (RCV000006175) (Uchida et al. 2004)
.0022 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 29-BP DEL, NT291] (rs387906345) (gnomAD:rs387906345) (RCV000006176) (Peyvandi et al. 2004)
.0023 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 1-BP INS, 4143A] (RCV000006163) (Peyvandi et al. 2004)
.0024 Thrombotic thrombocytopenic purpura, hereditary [ADAMTS13, 6-BP DEL, NT2930] (rs387906346) (gnomAD:rs387906346) (RCV000006177) (Peyvandi et al. 2004)
.0025 Thrombotic thrombocytopenic purpura, hereditary, adult-onset [ADAMTS13, ARG1060TRP] (Camilleri et al. 2008: von Krogh et al. 2016; Joly et al. 2018; Van Dorland et al. 2019; Delmas et al. 2020)

(Note)
A number sign (#) is used with this entry because hereditary thrombotic thrombocytopenic purpura (TTP) is caused by homozygous or compound heterozygous mutation in the ADAMTS13 gene (604134), which encodes the von Willebrand factor (VWF; 613160)-cleaving protease (VWFCP).

See 235400 for a discussion of the hemolytic-uremic syndrome (HUS), which has signs and symptoms similar to those in thrombotic thrombocytopenic purpura.

Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome (USS), is a rare autosomal recessive thrombotic microangiopathy (TMA). Clinically, acute phases of TTP are defined by microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. Hereditary TTP makes up 5% of TTP cases and is caused mostly by biallelic mutation in the ADAMTS13 gene, or in very rare cases, by monoallelic ADAMTS13 mutation associated with a cluster of single-nucleotide polymorphisms (SNPs); most cases of all TTP (95%) are acquired via an autoimmune mechanism (see 188030). Hereditary TTP is more frequent among child-onset TTP compared with adult-onset TTP, and its clinical presentation is significantly different as a function of its age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice. In contrast, almost all cases of adult-onset hereditary TTP are unmasked during the first pregnancy of of a woman whose disease was silent during childhood (summary by Joly et al., 2018).

▼ Clinical Features
Upshaw (1978) described a female with congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia, indicating a factor important to platelet and red cell survival. The proband, an only child of unrelated parents, was born with rudimentary right radius and ulna and a lobster claw deformity of the right hand. For the first 12 years of life she had 6 to 10 episodes a year of high fever, petechial rash, severe thrombocytopenia, and severe anemia. She would respond dramatically to blood transfusion, whereas adrenocorticosteroids and splenectomy were of no avail. After age 12, the attacks decreased to 3 or 4 yearly.

The same disorder may have been present in the patient of Schulman et al. (1960), an 8-year-old girl who had thrombocytopenia which responded to transfusions of blood or plasma. Deficiency of a stimulating factor that is responsible for megakaryocyte maturation and platelet production was postulated. The family history was negative. The mother's plasma induced normal platelet responses, whereas the father's resulted in submaximal responses. The patient of Schulman et al. (1960) was studied by a number of physicians because she moved from city to city. Splenectomy was of no benefit. In 1965, after a 5-month period of thrombocytopenia during which she did not receive intravenous plasma infusions, she had a complex of symptoms resembling those of glomerulonephritis, which was confirmed by renal biopsy (Abildgaard and Simone, 1967). The symptoms remitted with the reintroduction of plasma therapy. In 1973, the patient had preeclampsia during a pregnancy that resulted in a full-term normal boy. McDonald (1977) also postulated deficiency of a thrombopoietin-like substance in this patient. Plasma saved in 1975 and 1976 from this patient had normal levels of fibronectin (Goodnough et al., 1982). Rennard and Abe (1979) demonstrated deficiency of cold-insoluble globulin (fibronectin) in the patient of Upshaw (1978) but not in 4 other patients with thrombotic thrombocytopenic purpura.

Koizumi et al. (1981) described a patient who had thrombocytopenia and microangiopathic hemolytic anemia that seemed to improve with plasma administration. The plasma concentration of fibronectin was normal and intravenous administration of fibronectin was of no benefit. Shinohara et al. (1982) reported the case of a Japanese girl with similar clinical features responsive to plasma infusions. Hemolytic anemia, thrombocytopenia, distorted and fragmented circulating red cells, and megakaryocytosis of the bone marrow were present from the newborn period. They called the condition 'congenital microangiopathic hemolytic anemia' and suggested it was different from thrombotic thrombocytopenic purpura.

Of 4 affected sibs (2 male, 2 female) described by Wallace et al. (1975), the disease was fatal in 3. Kirchner et al. (1982) described this disorder in mother and daughter. The daughter's illness, characterized primarily by renal insufficiency, was most compatible with adult hemolytic uremic syndrome, and the mother's illness, which included neurologic findings and fever, was most compatible with thrombotic thrombocytopenic purpura. Merrill et al. (1985) reported 2 certain cases of thrombotic microangiopathy and 3 possible ones in 2 generations of a North Carolina black family. All affected members presented with acute renal failure and accelerated hypertension.

Kinoshita et al. (2001) reported 2 unrelated girls with onset of symptoms of USS at ages 4 years and 11 months, respectively. One of the girls developed a right hemiparesis caused by thrombotic occlusion of the left internal carotid artery at the age of 11 years. Both girls had received fresh frozen plasma infusion every 2 weeks.

Levy et al. (2001) studied 4 pedigrees with TTP. All patients presented at birth, except for 2 who experienced their first episode of TTP at ages 4 and 8 years; however, both of these individuals had sibs with disease onset as neonates. All patients had a chronic relapsing course and responded to plasma infusion. Activity of von Willebrand factor-cleaving protease (VWFCP) (see PATHOGENESIS) was measured in the plasma of 7 affected individuals and was found to be 2 to 7% of normal; none of the patients tested positive for inhibitors. Plasma levels of the protease in the parents of the affected individuals were 0.51 to 0.68 units/ml, consistent with a heterozygous carrier state. Levels for at-risk sibs of the patients and parents fell into a bimodal distribution, with one peak consistent with carriers and the other indistinguishable from the normal distribution.

Moake (2002) reviewed thrombotic microangiopathies. Familial TTP is associated with plasma levels of ADAMTS13 activity less than 5% of normal. The disease usually presents in infancy or childhood but sometimes is not evident until much later (Furlan and Lammle, 2001). Autoantibodies against ADAMTS13 are found in some cases of acquired idiopathic TTP. There is an association with the drug ticlopidine.

Upshaw-Schulman syndrome (USS) was originally reported as a disease complex with repeated episodes of thrombocytopenia and hemolytic anemia that quickly responded to infusions of fresh frozen plasma. Clinical signs often develop in the patients during the newborn period or early infancy. Indeed, the earliest and most frequently encountered clinical manifestation is severe hyperbilirubinemia with negative Coombs test soon after birth, which requires exchange blood transfusions. Pediatric hematologists had long been more familiar with this disease than general physicians, and a variety of alternative designations were given to the disease, such as chronic relapsing TTP, congenital microangiopathic hemolytic anemia (MAHA), and familial TTP/HUS, the last because the features of thrombotic thrombocytopenic purpura were almost indistinguishable from those of hemolytic-uremic syndrome (235400) (Matsumoto et al., 2004).

Kremer Hovinga and George (2019) reviewed the diagnosis, pathogenesis, and treatment of hereditary thrombotic thrombocytopenic purpura. Precipitants include birth (severe neonatal jaundice), alcohol excess, and especially pregnancy, with early loss and eclampsia in the first or second trimester. Data on long-term outcomes were lacking.

Adult-Onset Hereditary TTP
Fujimura et al. (2008) reported 9 Japanese women from 6 families with genetically confirmed USS who were diagnosed with the disorder during their first pregnancy. Six of the 9 had episodes of thrombocytopenia during childhood misdiagnosed as autoimmune idiopathic thrombocytopenic purpura (AITP; 188030). Thrombocytopenia occurred during the second to third trimesters in each of their 15 pregnancies, often followed by TTP. Of 15 pregnancies, 8 babies were stillborn or died soon after birth, and the remaining 7 were all premature except 1, who was born naturally following plasma infusions to the mother that had started at 8 weeks' gestation. All women had severely deficient ADAMTS13 activity. Fujimura et al. (2008) emphasized the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.

Joly et al. (2018) reported 22 patients from 20 families with adult-onset congenital TTP from the French registry for thrombotic microangiopathy (TMA). In all patients, TTP was triggered by pregnancy; none had any TMA symptoms at birth, in childhood, or outside of any obstetrical context. BY ELISA, 11 of 20 patients tested had detectable although very low levels of ADAMTS13 antigen (0.034-0.201 microg/ml). ADAMTS13 activity was measurable (between 3 and 10 IU/dL) in 10 of 17 patients tested, and 3 patients recovered a detectable ADAMTS13 activity ranging from 12 to 20 IU/dL in remission phase several years after the inaugural pregnancy-induced acute TTP episode.

Kremer Hovinga and George (2019) noted that adult-onset hereditary TTP is most often precipitated by pregnancy. The authors briefly described 2 patients with adult-onset hereditary TTP, one an 18-year-old man who presented with abdominal pain and vomiting for several days after excessive alcohol intake, and the other a previously healthy 34-year-old woman who presented with sudden vision loss due to serous retinal detachment in the thirteenth week of her first pregnancy.

Hamroun et al. (2020) reported that 5 women with known hereditary TTP (diagnosed in a first complicated pregnancy) were able to have 8 successful pregnancies with weekly monitoring of blood count and administration of plasma if platelet count was less than 150,000. In response, Kremer Hovinga and George (2020) reported that because complications of hTTP had been reported as early as 7 weeks' gestation, they began plasma prophylaxis as soon as pregnancy was confirmed. They began with 10 to 15 ml/kg every 2 weeks initially, and then weekly in the second trimester or sooner, if the woman's platelet count dropped. Their goal was to maintain the woman's platelet count at her normal level, which could be higher than 150,000 per cubic millimeter.

▼ Inheritance
Furlan et al. (1997) reported 2 brothers with chronic relapsing TTP who were deficient in the VWF-cleaving protease. In addition to these brothers, Furlan et al. (1998) found complete protease deficiency in 3 sibs: 2 sisters had their first episode of TTP during pregnancy, whereas their protease-deficient brother was asymptomatic for the disorder. Three further unaffected sibs of the family (2 brothers and 1 sister) had normal activity of VWF-cleaving protease. A third family with 2 affected brothers was reported. No consanguinity was established in any of the 3 families Furlan (1999). Autosomal recessive inheritance of the disorder was suggested.

▼ Diagnosis
Kremer Hovinga and George (2019) pointed out that the patient's age may help distinguish between acquired and hereditary TTP, with acquired TTP being much less common in young children than in adults. The presence of a functional ADAMTS13 inhibitor or an increased anti-ADAMTS13 immunoglobulin G (IgG) antibody titer argues against the diagnosis of hereditary TTP. An important clue in the diagnosis of hereditary TTP is the persistence of severe ADAMTS13 deficiency in remission. Additionally, patients with hereditary TTP may experience a transient ischemic attack (TIA) without thrombocytopenia or evidence of hemolysis. Thrombocytopenia may not be severe, and patients may present with acute kidney injury. Finally, patients with hereditary TTP recover rapidly after 1 or a few plasma exchanges.

▼ Pathogenesis
Moake et al. (1982) found unusually large multimers of von Willebrand factor (ULVWFMs) in the plasma of 4 patients, including the girl reported by Schulman et al. (1960), with chronic relapsing thrombotic thrombocytopenic purpura and proposed that these are the 'agglutinative' substances. These unusually large multimers are even larger than the largest multimers of VWF in normal plasma and resemble a subgroup of huge VWF forms secreted by human endothelial cells. After retrograde secretion by endothelial cells, these unusually large multimers become entangled in subepithelial fibrous components, thereby maximizing VWF-mediated adhesion of platelets to subendothelium after vascular damage. Normally, a processing activity in plasma prevents the highly adhesive, unusually large multimers from going far or staying long after being secreted into the bloodstream. Moake (1998) proposed that patients with chronic relapsing thrombotic thrombocytopenic purpura have a defect in the processing of these unusually large multimers that makes them susceptible to periodic relapses.

Furlan et al. (1996) and Tsai (1996) independently reported that a metal-containing proteolytic enzyme (metalloprotease) in normal plasma cleaves the peptide bond between tyrosine at position 842 and methionine at position 843 in monomeric subunits of VWF, thereby degrading the large multimers. This von Willebrand factor-cleaving protease was found by Furlan et al. (1997) to be deficient in 4 patients with chronic relapsing thrombotic thrombocytopenic purpura, 2 of whom were brothers. Because no inhibitor of the enzyme was detected in plasma, the deficiency was ascribed to an abnormality in the production, survival, or function of the protease.

Furlan et al. (1998) studied plasma samples from 30 patients with TTP and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial TTP, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor of VWF found in 20 of the 24 patients (in all 5 plasma samples tested) was shown to be an IgG antibody. Furlan et al. (1998) found that 6 patients with familial TTP lacked VWFCP activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was found to function normally in all 12 patients. Furlan et al. (1998) concluded that nonfamilial TTP is due to an inhibitor of VWFCP, whereas the familial form is caused by a constitutional deficiency of the protease. Patients with the hemolytic-uremic syndrome do not have a deficiency of VWFCP or a defect in von Willebrand factor that leads to its resistance to protease.

Tsai and Lian (1998) found severe deficiency of von Willebrand factor-cleaving protease in 37 patients with acute thrombotic thrombocytopenic purpura. No deficiency was detected in 16 samples of plasma from patients in remission. Inhibitory activity against the protease was detected in 26 of 39 plasma samples obtained during the acute phase of the disease. The inhibitors were IgG antibodies.

Tati et al. (2013) demonstrated deposition of complement C3 (120700) and C5b (120900)-C9 (120940) in renal cortex of 2 TTP patients using immunofluorescence microscopy and immunohistochemical analysis, respectively. Flow cytometric analysis showed that plasma from TTP patients contained significantly higher levels of complement-coated endothelial particles than control plasma. Histamine-stimulated glomerular endothelial cells exposed to patient platelet-rich plasma or patient platelet-poor plasma combined with normal platelets induced C3 deposition, via the alternative pathway, on VWF platelet strings and on endothelial cells in an in vitro perfusion system under shear conditions. No complement was detected when cells were exposed to control plasma or to patient plasma treated with EDTA or that had been heat-inactivated. Tati et al. (2013) concluded that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and endothelium and may contribute to thrombotic microangiopathy.

▼ Clinical Management
In the 2 patients with USS reported by Kinoshita et al. (2001), Yagi et al. (2001) studied the relationship between ULVWFMs and thrombocytopenia by analyzing platelet aggregation using a mixture of the patients' plasma and normal washed platelets under high shear stress. There was a remarkably enhanced high shear stress-induced platelet aggregation by the patients' plasma, which was almost completely normalized by administration of fresh frozen plasma. The results indicated that thrombocytopenia in USS patients is caused by a combination of the presence of ULVWFMs, platelets, and high shear stress generated in the microcirculation.

Vesely et al. (2003) stated that initial management of patients with TTP is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. They performed a prospective study of ADAMTS13 activity in 142 consecutive patients, making measurements before beginning plasma exchange treatment. Severe ADAMTS13 deficiency, defined in this study as ADAMTS13 activity levels less than 5% of normal, was found in 18 (13%) of the 142 patients; it occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. Among the 48 patients with idiopathic TTP, the presenting features and clinical outcomes of the 16 who had severe ADAMTS13 deficiency were variable and not distinct from the 32 who did not have severe ADAMTS13 deficiency. Patients at all levels of ADAMTS13 activity apparently responded to plasma exchange treatment.

In a review, Kremer Hovinga and George (2019) noted that plasma infusions were used to treat acute episodes and chronically in patients with recurrent symptoms. They also discussed the institution of at-home recombinant human ADAMTS13 to treat this condition.

Joly et al. (2018) stated that while their child-onset USS patients exhibited a severe disease characterized by a 47% rate of ischemic sequelae and a high frequency of relapses requiring efficient prophylactic plasma therapy in 82% of cases, their adult-onset patients (who were exclusively pregnancy-induced) had no relapse and no requirement for plasma prophylaxis outside of an obstetrical context.

▼ Mapping
Levy et al. (2001) used the plasma levels of VWF-cleaving protease as a phenotypic trait for linkage analysis. They analyzed DNA from affected individuals and other informative family members using 382 polymorphic microsatellite markers. A lod score of 5.63 at theta of 0.0 was obtained for marker D9S164 on 9q34 using a codominant model. Multipoint analysis for D9S164 and 4 flanking markers yielded a maximum lod score of 7.37 at marker D9S164.

▼ Molecular Genetics
By analysis of genomic DNA from patients with familial TTP, Levy et al. (2001) identified 12 mutations in the ADAMTS13 gene (604134.0001-604134.0012), accounting for 14 of the 15 disease alleles studied. Levy et al. (2001) demonstrated that deficiency of ADAMTS13 is the molecular mechanism responsible for thrombotic thrombocytopenic purpura and suggested that physiologic proteolysis of von Willebrand factor and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

In 2 Japanese families with Upshaw-Schulman syndrome, characterized by congenital TTP with neonatal onset and frequent relapses, Kokame et al. (2002) reported 4 novel mutations in the ADAMTS13 gene (604134.0013-604134.0016). Activity of von Willebrand factor-cleaving protease was less than 3% of normal in all probands; VWFCP activity in heterozygous parents ranged from 30 to 60%.

In a patient with USS and severely reduced levels of VWFCP activity, Savasan et al. (2003) identified a homozygous mutation in the ADAMTS13 gene (604134.0017).

Of 22 patients with adult-onset congenital TTP studied by Joly et al. (2018), all with pregnancy-triggered disease, 18 (82%) carried the arg1060-to-trp (R1060W) mutation (604134.0025), 3 in homozygosity and 15 in heterozygosity.

Van Dorland et al. (2019) presented data on 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017. Disease onset ranged from birth to 70 years of age. All patients were considered biallelic for mutated ADAMTS13; a table listed 47 homozygotes and 76 compound heterozygotes, but in the text it was stated that in 1 patient, whose phenotype was confirmed by a plasma infusion trial, only 1 mutation could be found. The most frequent mutation was c.4143_4144dupA (604134.0023), present on 60 of 246 alleles, followed by R1060W (604134.0025) on 13 of 246 alleles.

▼ History
Moschcowitz (1924) described the abrupt onset of petechiae and pallor, followed rapidly by paralysis, coma, and death, in a 16-year-old girl. At autopsy, terminal arterioles and capillaries were occluded by hyaline thrombi, later determined to consist mostly of platelet without perivascular inflammation or endothelial desquamation. Moschcowitz (1924) suspected a 'powerful poison which had both agglutinative and hemolytic properties' as the cause of this disorder, now known as thrombotic thrombocytopenic purpura.

(文献)
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() Joly, B. S., Boisseau, P., Roose, E., Stepanian, A., Biebuyck, N., Hogan, J., Provot, F., Delmas, Y., Garrec, C., Vanhoorelbeke, K., Coppo, P., Veyradier, A. ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age-onset in the French cohort of Upshaw-Schulman syndrome. Thromb. Haemost. 118: 1902-1917, 2018
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() van Dorland, H. A., Taleghani, M. M., Sakai, K., Friedman, K. D., George, J. N., Hrachovinova, I., Knobl, P. N., von Krogh, A. S., Schneppenheim, R., Aebi-Huber, I., Butikofer, L., Largiader, C. R., and 11 others. The International Hereditary Thrombotic Thrombocytopenic Purpura registry: key findings at enrollment until 2017. Haematologica 104: 2107-2116, 2019

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